Process for producing gamma-halogen gamma-aceto propyl alcohol



Patented Mar. 23, 1943 UNITED STATES This invention relates to theproduction of halogenated derivatives of aceto propane and has for itsobject the provision of new and useful derivatives of this nature anduseful and efiective methods of making them. Halogenated derivatives ofthe type to which this invention relates are useful in the synthesis ofvitamin B1, which has extremely valuable therapeutic and nutritionalproperties.

This application is a division of my copending application Serial No.296,816 filed September 27, 1939, [for Halogenated derivatives of acetopropane, which in turn was filed as a continuation in part of myapplications, Serial No. 118,573, filed December 31, 1936, and SerialNo. 171,905, filed October 30, 1937. Application Serial No. 118,573 wasa division of application Serial No. 98,929, which I filed September 1,1936, while application Serial No. 171,905 was a continuation in part ofapplication Serial No. 11,683, which I filed March 18, 1935, and of saidapplication Serial No. 98,929.

In the foregoing applications the product obtained by halogenating 'yaceto propyl alcohol or by hydrolysing halogenated a aceto 'ybutyrolactone is described as v halogen -y aceto propyl alcohol butithas been subsequently found that molecules of a 'y halogen 'y acetopropyl alcohol tend to react spontaneously with one another to formhalogenated aceto propyl ethers with surprising ease. These ethers whenin aqueous solutions hydrolize into the halogenated alcohol more or lesscompletely according to the concentration and temperature. When 7halogen 'y aceto propyl alcohol is distilled, the resulting product mayconsist predominantly of either the alcohol or the ether depending uponthe temperature, pressure and/or speed of the distillation. Theconditions for isolation described in the above mentioned applicationsare such as to produce,

in whole or in part, the ether rather than the alcohol.

There are three possible forms in which 'y aceto propyl alcohol mayexist, the formulae of which may be written:

()H HaC--C=CHC HCH:O H (enolic form), and

r (inner ether, lactone, or 7 H3O GET-CH2 tetrahydrofurane form) PROCESSFOR PRODUCING GAMMA-HALO- GEN GAMMA ACETO PROPYL ALCOHOL Edwin R.Buchnian, Pasadena, Calif., assignor to Research Corporation, New York,N. Y., a corporation of New York No Drawing. Original applicationSeptember 27,

1939, Serial No. 296,816. Divided and this application August 21, 1940,Serial No. 353,504

7 Claims. (01. Zea-594) It is probable that any solution of this productcontains some or all of these forms in equilibrium, The above outlinedketonic form undoubtedly is in 'tautomeric equilibrium with the enolicform of the molecule. These tautomeric forms are, however, so readilyinterconvertible, in harmony with enol-keto tautomers in general, thatfor the sake of simplicity the enolic forms will be ignored in thefollowing discussion.

The several halogen derivatives of v aceto propyl alcohol likewise mayexist in similar (ink-on v VII m on3oo-onx onzonz-o-d-o-onlaux-0H2 VIIIin which formulae, X has the same significance as before. It isdifficult to determine which of these forms the ether will assume underany given set of conditions, but it appears that the form usuallyobtained under, ordinary conditions,

as in the specific examples given hereinafter,

possesses one tetrahydrofurane radical and has the structure indicatedby Formula VIII.

In the aforementioned application Serial No. 171,905, I have describedseveral methods of making halogen derivatives of 'y aceto propyl alcoholand have described the properties of the.

. resulting products. Several products of reaction which boil over therange from 84 to C. at l to 2 mm. pressure are described therein and,while halogen derivativesof 'y aceto propyl alcohol undoubtedly arepresent in the reaction mixtures obtained by halogenation of v acetopropyl alcohol, one of the above described halogenated ethers is theprincipal product obtained upon distillation under the conditionsdescribed,

instead of the corresponding halogenated alcohol as stated in mypreviousapplications re:

ferred to hereinabove. However, for all practical purposes, the desiredresult is obtained no matter which compound is secured because in thepresence of traces of water the ether reacts as if the alcohol wereused. For example, if the product is dissolved in water, a solutioncontaining halogenated aceto propyl alcohol is obtained. Since theprincipal intended use of the product is in the synthesis of thethiazole portion of vitamin B1 and in such synthesis water is present oris formed in the course of the reaction, the particular product isolatedis more or less immaterial except from a theoretical standpoint. Becausethe ether is more stable than the alcohol, it is preferable from apractical standpoint to employ the ether.

In accordance with the present invention, a halogenated derivative ofaceto propane may be prepared by the halogenation of 'y aceto propylalcohol with one of the elemental halogens bromine, chlorine and iodineor with sulphuryl bromide or sulphuryl chloride. The same halogenatedderivative may likewise be made by halogenating a aceto 'y butyrolactonewith one of the same halogenating agents and then subjecting theresulting 'y halogenated butyrolactone to a combined hydrolysis anddecarboxylation. The reaction product is then treated in a suitablemanner to remove the desired product, or products, which may be ahalogen derivative of 'y aceto propyl alcohol, a halogen derivative ofaceto propyl ether, or both, depending upon the isolation process.

The invention will be fully understood from the following detaileddescription of specific embodiments thereof. As an example of how theinvention may be practiced, 'y aceto propyl alcohol may be halogenatedby treatment with a suitable halogenating agent, such as a halogen or asulfuryl halide.

Example 1 In accordance with one specific embodiment of the invention, 7brom 'y aceto propyl alcohol, which may also be designated3-brom-3-acetopropan-l-ol, may be prepared by dissolving 30 grams of vaceto propyl alcohol in 150 cc. of Water and vigorously stirring thesolution While 48 grams of bromine are added drop by drop at such a ratethat the color imparted to the solution by one drop of the brominedisappears before the next drop is added. The aqueous solution whichresults contains impure 'y brom v aceto. propyl alcohol.

One method of purifying the product is to separate the small-amount ofinsoluble oil which is formed as: a by product, from the aqueoussolution and to extract the aqueous solution repeatedly with ordinaryethyl ether to dissolve the remainder of the brominated product. Theinsoluble oil and the ethereal extracts are combined and dried. over asuitable dehydrating agent such as anhydrous sodium sulfate. The ethylether is then distilled off and the residue is practically pure di.(brom aceto propyl) ether which is hereinafter designated brom aceto.propyl other This material may be further purified, if desired, by'distilling it in vacuo at less than 1 mm. of mercury. The product is acolorless oil, which is soluble in hot water, ether and alcohol andwhich may be distilled though not without some decomposition. The puresubstance can be readily distilled in a molecular still at 40 C. bathtemperature and at 0.008 mm. pressure. Calcd. for: CroHrsOaBlz. mol.

, ings are extracted with ethyl ether.

wt.=343.96; 0:34.89; H=4.69. Found: mol. wt: 316 (dioxane) C 34.84; H4.56. d =1.592 gm./cc. n n=1.4989.

The brom aceto propyl ether thus prepared is sparingly soluble in waterbut freely soluble in organic solvents such as petroleum ether. It maybe converted into 'y brom v aceto propyl alcohol by making a dilutewater solution thereof, for it hydrolizes readily into the brominatedalcohol. The solution of the ether in water may be most readily effectedby mild heating at a temperature of 50 to 60 C. The brom alcohol has notbeen isolated as such because it goes over into the ether too readily.However, the presence of the alcohol in a water solution of the bromether has been established by freezing point depression of the aqueoussolution.

Example 2 The corresponding chlorine derivatives may likewise be made bydirect reaction of chlorine upon 7 aceto propyl alcohol. Thisreactionmay be carried out by treating 12 grams of 'y aceto propylalcohol, dissolved in 60 cc. of Water, with a stream of gaseouschlorine, the reaction mixture being stirred and cooled if necessary sothat the temperature remains between 20 C. and 40 C. This is continueduntil the increase in weight of the reaction mixture reaches 8 /2 grams.The mixture is cooled to about 15 C. and allowed to stand 15 minutesduring which time a small, heavy oily lay-er separates at the bottom ofthe vessel. This oily layer is removed and washed twice with water. Theaqueous layer and the aqueous wash- Then the ethereal extracts arecombined with the above oily layer and dried over a suitable dehydratingagent, such as sodium sulfate. The ethyl ether is evaporated off leavingan oil boiling at 87 to C. at about 2 mm. pressure. This material is astable, colorless oil which is soluble in ether, alcohol and hot waterand is slightly soluble in cold water. This product consists principallyof chlor aceto propyl ether having the properties described in Exampl 5below.

The invention also contemplates the production of the related iodinederivatives in a similar manner, although iodine is not so reactive asbromine or chlorine and the yield of the iodine compounds is not sogreat.

Instead of using halogens as the halogenating agents, suliuryl halides,such as sulfuryl chloride or sulfuryl bromide may be employed.

Example 3 In practicing one process of this nature, 27 rams of sulfurylchloride are added slowly to 20.4 grams of 'y aceto propyl alcohol andthe reaction mixture is kept at 0 C. for one-half hour. At the end ofthat time, 50 cc. of ethyl ether are added and the mixture is heated toexpel the sulfur dioxide and the hydrogen chloride remain-.

distilled in vacuo to remove the petroleum ether and th residue isfractionally distilled in vacuo, whereupon a product having a boilingpoint at 2 mm. pressure of about 90 to C. is obtained.

This product also consists predominately oi the aforementioned chloraceto propyl ether.

The corresponding brom compounds may be prepared in a similar manner byreacting upon 'y aceto propyl alcohol with an equivalent amount ofsulfuryl bromide and purifying the product obtained by a similarprocedure.

} The brom, chlor and iodo derivatives of aceto propane describedhereinbefore may also be made by simultaneously hydrolizing anddecarboxylating the corresponding a halogen dervative of a aceto 'ybutyrolactone. The a aceto 'y butyrolactone employed in this reactionhas the formula onto eel-cu,

and may be prepared in accordance with the method described in thearticle by I. L. Knunyants, G. V. Chelintzev and E. D. Osetrova,published in Compt. 'Rend. Acad. Sci. U. S. S. R. n. s. 1, 315-317(1934) and referred to in Chemical Abstracts 28, 4382 (1934). Thisreaction is carried out by causing ethyl aceto acetate to react withethylene oxide in the presence of either sodium ethylate or sodiummethylate, th latter being preferred.

Example 4 Chlor aceto propyl ether may be obtained by first preparing achlor a aceto v butyrolactone by treating a aceto v butyrolactone withsulfuryl chloride, in accordance with the method described in myaforesaid application Serial No. 118,573, now

Patent No. 2,193,858, issued March 19, 1940.

In carrying out this reaction 68 grams of the a aceto '7 butyrolactoneare placed in a flask equipped With a mechanical stirrer and 68 rams ofsulfuryl chloride are added with continual stirring over a period of oneand a half hours. After the reaction is completed the reaction productis washed with Water, taken up in ether and dried over a suitabledehydrating agent, such a calcium chloride. The ethereal extract is thendistilled at a reduced pressure and the fraction distilling atapproximately 85 C. and 2 or 3 mm. pressure is collected. This productis substantially pure or chlor a aceto 'y butyrolactone having theformula:

cine o cut-om C/ 01 o 81 grams of this chlor lactone, 80 cc. of waterand cc. of concentrated hydrochloric acid are then mixed and heatedunder a reflux condenser at 100 C. for 75 minutes. By this treatment thechlor'butyrolactone is simultaneously hydrolyzed and decarboxylated inaccordance with the following equation:

01130 O OKs-CH2 C Cl (%-0 A similar result is obtained by using a dilutesolution of an alkali instead of the dilute acid. The acid and alkali arboth examples of pH modifying agents.

The reaction mixture is then extracted several times with small portionsof ethyl ether and the combined ethereal solution is dried over adehydrating material, such as sodium sulphate. The dried solution isthen distilled in vacuo and the portion boiling at to C. at 2 to 3 mm.pressure is collected. The collected material is principally chlor acetopropyl etherand is substantially identical with the product obtained bydirect chlorination of 'y aceto propyl alcohol and distillation of thereaction produc as described in Example 2. a

\ Example 5 410 grams of the chlorinated lactone prepared as describedin Example 4 are heated on a steam bath with 410 cc. of water and 12 cc.of 38% hydrochloric acid until decarboxylation is complete. Thisoperation requires about 7 hours. On cooling the reaction mixture anoily layer separates which is removed by repeated extraction of themixture with petroleum ether. The ether extracts are then shaken withsolid potassium carbonate to remove any acid, the potassium car bonateis filtered oiT, the solvent is removed by means of a water pump and theremaining oil is fractionally distilled. The fraction boiling at 68? C.to C. at a pressure of 1 mm. is collected and upon redistillation ofthis fraction pure chlor aceto propyl ether is obtained from thedistillate boiling at 110 to 112 at 1 mm. pressure. Calcd forC10H1603C121 mol. wt.:255.06; 0:47.04; 11:6.32 and 01:27.81. Found: mol.wt. 259 (dioxane); C:47.13; 11:6.13; and Cl:28.07. d :l.2175 gm./cc. n:1.4=748.. This chlor aceto propyl ether is a colorless and almostodorless liquid which is soluble with difficulty in water but which isreadily soluble in organic solvents.

Example 6 If the oily liquid described in Example 5 is fractionallydistilled at 1.7 mm. pressure and that fraction which is obtained at 68to 70 C. is redistilled at 3 1() mm. at 20 to 24 C., a fraction isobtained consisting of 'y chlor 'y aceto propyl alcohol. Calcd forC5H902C1; mol. wt.: 136.54; 0:43.95; H:6.64; and 01:25.96. Found: mol.wt.:146(dioxane); 0:44.64; H:6.29 and Cl:26.43. d ":1.2l0 gm./cc. n:1.4684. This chlor aceto propyl alcohol is insoluble in petroleumether, whereas the chlor aceto propyl ether is soluble therein.

If, however, this low boiling fraction is redistilled at 1.7 mm.pressure, most of the distillate boils in the ether range, that is about120 C. with splitting off of' water, which can be collected in a carbondioxide trap. Thus, it is evident that both chlor aceto propyl alcoholand chlor aceto propyl ether may be obtained from the same reactionmixture and that therproduct isolated depends upon the conditions whichexist during the'isolation step.

Aqueous solutions of chlor aceto propyl ether give molecular weightvalues indicating complete hydrolysis into chlor aceto propyl alcohol.The ether goes into water solution readily when the mixtures are warmed,60 C. having proved to be a satisfactory temperature to employ.

Example 7 5 grams of chlor aceto propyl ether, prepared by any of theforegoing processes are heated with 500 cc. of water at 60 C. for aboutsix hours and the mixture is allowed to stand. All of the resulting oilylayer will dissolve upon shaking the mixture. The mixture is extractedrepeated with ether, the ethereal extracts are dried over a suitabledehydrating agent, such as sodium sulfate, and the solvent is thenremoved in a water pump at 200 C. The residual oil is then fractionallydistilled in a molecular still and 'y chlor 7 aceto propyl alcohol,boiling at 27 C. at 0.01 mm. pressure is obtained. Calcd for C5H902Cl:mol. \vt.=136.54; :43.95; II=6.64 and 01:25.97. Found: apparent mol.wt.:1l8.5; corrected for mol. of water consumed in the hydrolysis wouldgive mol. wt.=127.5; 0:44.35; H=6.48. d =1.210 gm./cc. 1r =1.4684. Thechlor aceto propyl alcohol is insoluble in petroleum ether, while chloraceto propyl ether dissolves therein readily.

The bromine compound which corresponds to the chlorinated lactonedescribed hereinabove in Example 4 may be made in an analogous manner bytreating a aceto 'y butyrolactone with sulphuryl bromide or in aqueoussuspension with bromine. The bromide compound corresponding to the abovedescribed chlorinated aceto propyl alcohol may then be prepared bytreating the brominated lactone with a suitable pH regulating agent,such as dilute hydrobromic acid.

Example 8 These reactions may be carried out by suspending 32 grams or"a aceto v butyrolactone in 70 cc. of water and adding 40 grams ofbromine thereto drop by drop, meanwhile vigorously stirring the mixturewith a mechanical stirrer. This will produce a bromo a aceto 'ybutyrolactone and in the reaction which occurs hydrobromic acid is alsoproduced. This brominated lactone may be hydrolyzed and decarboxylatedby means of a dilute solution of hydrobromic acid. Since hydrobromicacid is present in the reaction mixture resulting from the brominationof the lactone, the simplest way to hydrolyze the brominated lactone isto continue to stir the mixture after the bromine has been added, untilthe hydrolysis and decarboxylation are completed. The brominated productresulting from the hydrolysis is extracted from the mixture with ether,and the ethereal extract is dried. The dried extract is freed from ethylether and is then distilled in vacuo at about 1 mm. pressure and thebrom aceto propyl ether is collected. This material is an oil which iscolorless when freshly made, but it is not as stable as thecorresponding chlorine compound and darkens on standing.

The corresponding 7 iodo 'y aceto propyl alcohol and iodo aceto propylether may be produced in smaller yields than the related chlor and bromcompounds by employing elemental iodine in-- stead of the chlorinatingand brominating agents mentioned previously in the several reactionsdescribed hereinabove. If desired, the iodo compound may also beprepared in more substantial yields, by treating one of the chlor orbrom alcohols or ethers with sodium iodine.

As stated previously, the halogenated aceto propyl ethers obtained mayassume the structures indicated by Formulae VI, VII, and VIII outlinedhereinabove. If VI were the correct structure, one would expect that twomolecules of phenyl hydrazine would react with 1 molecule of thedihalo-aceto-propyl ether. If the correct structure were VII phenylhydrazine would not react with this ether at all. Actually, in fullagreement with structure VIII, only 1 molecule of phenyl hydrazinereacts with 1 molecule of the ether. When a second molecule of phenylhydrazine is present, it separates from the reaction mixture as phenylhydrazine hydrochloride. The product of reaction of phenyl hydrazinewith 'y halogen 'y aceto propyl other is analogous in structure to"tetraphenyltetracarbazon" described by Sven Bodforss in Berichte derdeutschen chemischen Gesellschaft, vol. 52, p. 1762 and 1767 (1919)'andvol. 72, p. 468 (1939). The reaction involved is also analogous to thatof Bodforss but only one side of the molecule undergoes reaction withphenyl hydrazine. Thus the product of the action of phenyl hydrazine on'y chloro 7 aceto propyl ether having the properties described inExample 5 is a yellowish crystalline powder melting at about C.,insoluble in water or petroleum ether, but soluble in other usualorganic solvents, such as alcohol, acetone or ether. It has acomposition corresponding to the formula According to the later ideas ofBodforss, its structure is as follows:

If an excess of phenyl hydrazine is used in the above reaction and aninert solvent is employed, the excess of the reagent is unchangedshowing the presence of one and only one a chlor keto group in themolecule of the 'y chloro 'y aceto propyl ether. This is furtherconfirmed by the action of iodine on an aqueous alkaline solution of 'ychloro 'y aceto propyl ether. If this reaction is carried out with acold water solution only half as much iodine is consumed as is the casewhen the 'y chloro 'y aceto propyl ether is first warmed with Water fora few minutes before carrying out the iodine reaction. This is evidencethat the ether has only one -COCH3 group and that another such group isformed when the ether is hydrolyzed into the related alcohol.

From the foregoing, it is apparent that the halogenated aceto propylethers produced as described hereinbefore contain at least onetetrahydrofurane group and that in all probability they contain only onesuch group. However, the appended claims are intended to embrace allforms of the ether unles specifically limited to cover only certain onesof such ethers.

The chlorine, bromine and iodine derivatives of aceto propyl alcohol andether produced in accordance with the invention may be condensed withthio formamide to produce salts of the thiazole derivative known asl-methyl-fi-(fi-hydroxy-ethyl) thiazole in accordance with the methodoutlined in Patent No. 2,133,966 granted October 25, 1938. This thiazolederivative may in turn be caused to enter into other reactions toproduce synthetic compounds having the. characteristic physiological andtherapeutic properties of the antineuritic vitamin.

What is claimed is:

1. Process of producing a 'y halogen 'y aceto propyl alcohol whichcomprises treating a dihalogen 'y aceto propyl other with water.

2. Process of producing 'y brom 'y aceto propyl alcohol which comprisestreating a di- 7 brom 'y aceto propyl ether with water.

3. Process of producing 'y chlor v aceto propyl alcohol which comprisestreating a di- 1/ chlor 1 aceto propyl ether with water.

a. Process of producing 'y iodo 'y aceto propyl alcohol which comprisestreating a di- 7 iodo aceto propyl ether with water;

7. The process of producing a 'y halogen 'y aceto propyl alcohol whichcomprises heating a di- 7 halogen 'y aceto propyl ether with Water at atemperature of about 50 C. to 60 C.

EDWIN R. BUCHMAN.

